M1 Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M3 Receptor Knockout Mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 304; no. 2; pp. 675 - 682
• Main Authors: Stengel, Peter W, Cohen, Marlene L
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.02.2003
• Subjects: Animals; Cyclooxygenase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Electric Stimulation - methods; Gastric Fundus - drug effects; Gastric Fundus - physiology; In Vitro Techniques; Male; Mice; Mice, Knockout; Muscarinic Agonists - pharmacology; Muscle Relaxation - drug effects; Muscle Relaxation - physiology; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - physiology; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Receptors, Muscarinic - deficiency; Receptors, Muscarinic - genetics; Receptors, Muscarinic - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.042283

Muscarinic receptors can mediate both contractile and relaxant responses in smooth muscle. The stomach fundus from wild-type mice possesses a neuronal M 1 receptor that mediates relaxation to carbamylcholine and (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343) but is masked by M 3 receptor-mediated contraction to both agonists. When the M 3 receptor was deleted, cholinergic-induced relaxation was unmasked. M 1 receptor antagonism with pirenzepine, nitric oxide (NO) synthase inhibition with N ω -nitro- l -arginine methyl ester hydrochloride, and inhibition of neuronal activation with tetrodotoxin abolished relaxation to McN-A-343 in tissues from M 3 receptor knockout mice, supporting the neuronal localization of an M 1 receptor that activated NO release to effect relaxation. However, the cyclooxygenase inhibitor indomethacin did not affect contraction or relaxation to carbamylcholine in stomach fundus from wild-type or M 3 receptor knockout mice, indicating that cyclooxygenase products played no role in these responses. The neuronal M 1 receptor modulated relaxation induced by carbamylcholine and McN-A-343 but not relaxation induced by electric field stimulation of the stomach fundus. These data support the presence of M 1 receptor-mediated relaxation in the stomach and suggest that when the M 3 receptor is eliminated or blocked, M 1 receptor-mediated gastric relaxation may be enhanced, possibly leading to alterations in gastric emptying and subsequent effects on body weight.